The present invention relates to drug delivery and diagnostic sampling and, in particular, it concerns systems and methods for the transport of fluids through a biological barrier and production techniques for such systems.
Various techniques are known for drug delivery. A first set of techniques employ oral delivery in the form of pills or capsules. Many drugs cannot, however, be effectively delivered orally due to degradation in the digestive system, poor absorption and/or elimination by the liver.
A second set of techniques deliver drugs directly across the dermal barrier using a needle such as with standard syringes or catheters. These techniques, however, require administration by one trained in their use, and often cause unnecessary pain and/or local damage to the skin. The withdrawal of body fluids for diagnostic purpose using a conventional needle suffers from the same disadvantages. The use of a conventional needle is also undesirable for long term, continuous drug delivery or body fluid sampling.
An alternative delivery technique employs a transdermal patch, usually relying on diffusion mechanisms. The usefulness of transdermal patches, however, is greatly limited by the inability of larger molecules to penetrate the dermal barrier. Transdermal patches are not usable for diagnostic purposes.
Many attempts have been made to develop alternative devices for active transfer of pharmaceutical materials, or for biological sampling, across the dermal barrier. For example, U.S. Pat. No. 5,250,023 to Lee et al. discloses a drug delivery device which includes a plurality of non-hollow microneedles having a diameter of 50-400 micron which perforate the skin to facilitate transfer of larger molecules through the dermal barrier. The microneedles are disclosed as being made of stainless steel.
More recently, much research has been directed towards the development of microneedles formed on chips or wafers by use of micro-machining techniques. This approach promises the possibility of producing numerous, very small needles which are sufficient to form small perforations in the dermal barrier, thereby overcoming the molecular size limitations of conventional transdermal patches, while being safe for use by unqualified personnel. Examples of such work may be found in PCT Publication No. WO 99/64580 to Georgia Tech Research Corp., as well as in the following scientific publications: “Micro machined needles for the transdermal delivery of drugs”, S. H. S. Henry et al. (MEMS 98, Heildelberg, Germany, January 1998); “Three dimensional hollow micro needle and microtube arrays”, D. V. McAllister et al. (Transducer 99, Sendai, Japan, June 1999); “An array of hollow micro-capillaries for the controlled injection of genetic materials into animal/plant cells”, K. Chun et al. (MEMS 99, Orlando, Fl., January 1999); and “Injection of DNA into plant and animal tissues with micromechanical piercing structures”, W. Trimmer et al. (IEEE workshop on MEMS, Amsterdam, January 1995). The more recent of these references, namely, the Georgia Tech application and the Chun et al. reference, disclose the use of hollow microneedles to provide a flow path for fluid flow through the skin barrier.
While hollow microneedles are potentially an effective structure for delivering fluids across the dermal barrier, the structures proposed to-date suffer from a number of drawbacks. Most notably, the proposed structures employ microneedles with flat hollow tips which tend to punch a round hole through the layers of skin. The punched material tends to form a plug which at least partially obstructs the flow path through the microneedle. This phenomenon is clearly visible in the scanning electron microscope (SEM) image identified as FIG. 11 of the Chun et al. reference and reproduced here as FIG. 1. This is particularly problematic where withdrawal of fluids is required since the suction further exacerbates the plugging of the hollow tube within the microneedle. The flat ended form of the needles also presents a relatively large resistance to penetration of the skin, reducing the effectiveness of the structure.
A further group of proposed devices employ microneedles formed by in-plane production techniques. Examples of such devices are described in U.S. Pat. No. 5,591,139 to Lin et al., U.S. Pat. No. 5,801,057 to Smart et al., and U.S. Pat. No. 5,928,207 to Pisano et al. The use of in-plane production techniques opens up additional possibilities with regard to the microneedle tip configuration. This, however, is at the cost of very limited density of microneedles (either a single microneedle, or at most, a single row of needles), leading to corresponding severe fluid flow rate limitations. The very long proposed needle (about 3 mm) of Smart et al. suffers from an additional very high risk of needle breakage.
A further shortcoming of microneedle structures made by micromachining techniques is the brittleness of the resulting microneedles. Microneedles made from silicon or silicon dioxide are highly brittle. As a result, a significant proportion of the microneedles may fracture due to the stresses occurring during penetration, leaving fragments of the material within the tissue. Furthermore, oblique insertion by an unskilled person could lead to fracture of a very large proportion of the needles, resulting in malfunction of the device.
There is therefore a need for devices and methods based on micro-machining technology for the transport of fluids through the dermal barrier which would reduce or eliminate the problems of blockage by the layers of skin. I would also be highly advantageous to provide devices of this type with highly flexible microneedles to avoid leaving fragments of the microneedles within the skin tissue. Finally, there is a need for practical devices and corresponding systems for implementing diagnosis and treatment of various conditions based on such technology.